Juvenile idiopathic arthritis (JIA), is the most common childhood arthropathy which affects hundreds of thousands of children in the United States and around the world. Although the evidence for a genetic predisposition to JIA is strong, success in identifying loci that influence susceptibility to JIA has hitherto been limited. Most prior studies have focused on case-control studies of unrelated individuals with JIA. Using Utah Population Database (UPDB) a unique genealogy database, we have identified several multigenerational families in which there are four to thirteen affected children with JIA. We propose to study distantly related individuals with JIA in these large pedigrees to test the hypothesis that distantly-related children with JIA will exhibit extended identity by descent (IBD) sharing in regions surrounding variants which predispose to JIA. We propose the following specific aims. Aim 1: Identify and characterize distantly related children with JIA in extended multiplex pedigrees. Using the UPDB we will identify additional extended pedigrees where the founders have a significantly higher risk of having descendants with JIA. We will select 200 cases with JIA that are distantly related to each other. Using our large cohort of autoimmunity free controls, we will similarly identify 100 distantly-related unaffected control individuals from a separate set of non-JIA pedigrees. Aim 2: Identify candidate genomic regions as revealed by excessive IBD sharing among JIA cases in extended multiplex pedigrees. We will use the Affymetrix 6.0 Array to genotype ~900K common single nucleotide polymorphisms (SNPs) in 200 distantly-related affected cases from the extended multiplex JIA pedigrees, and the 100 distantly-related unaffected controls. We will use the resulting genotypes to identify genomic regions with greater-than-expected IBD sharing between pairs of cases as compared to pairs of controls. We will generate a list of candidate genomic regions from within these IBD regions for subsequent validation in Aim 3. Aim 3: Validate high priority candidate genomic regions identified in Aim 2 in an independent case-control study of a cohort of 1000 JIA cases and 1000 matched controls. We will use the Illumina GoldenGate assay to genotype high-priority variants in regions with excessive IBD sharing identified in specific aim 2 in a well-characterized independent cohort of unrelated children with JIA and a large group of autoimmunity free healthy controls matched for ethnicity. Our proposal builds on existing well characterized cohorts of cases with JIA and controls, as well as several large multigenerational families with multiple affected children with JIA to identify genes associated with JIA susceptibility. We believe that applying high density genotype data and modern analytical approaches to familial cases of JIA offers an innovative approach to the identification of genetic variants predisposing to JIA. Identification of variants associated with JIA will improve the understanding of the pathophysiology of JIA, and improve the diagnosis and treatment of JIA. PUBLIC HEALTH RELEVANCE: We seek to identify genetic factors that cause juvenile idiopathic arthritis, a chronic painful condition that affects thousands of children. We will accomplish this by studying genetic variation in families we have identified with higher rates of juvenile idiopathic arthritis than expected. We will confirm the findings in other children with juvenile arthritis. Identification of the causes of juvenile arthritis will lead to improvements in the diagnosis and treatment of this chronic and debilitating condition.